This invention relates to a method and apparatus for reducing mineralization of a cardiovascular tissue in a subject, particularly to the use of an acid treatment solution for reducing mineralization of cardiovascular tissue such as a vessel or a valve.
Atherosclerosis is commonly understood to be a deposition of cholesterol in the vessels of the cardiovascular system. An additional significant complication is pathologic calcification, which takes place both in blood vessels and in heart tissue. Cardiovascular bioprostheses also host calcific deposits that may severely limit longevity and performance of the device. Calcium deposits have been shown to be calcium phosphates that contain several inorganic components such as carbonate, acidic phosphate, sodium, magnesium, and fluoride (Tomazic, B. B., et al., Ann. Thorac. Surg. 60(2 Suppl.):S322-S327, 1995). All deposits, regardless of the site of formation, are carbonated apatites that contain an appreciable fraction of carbonate (Tomazic, B. B., et al., Atherosclerosis 69:5-19, 1988). It has been suggested that octacalcium phosphate (Ca4H(PO4)3.2.5 H2O), could be a precursor mineral in the formation of cardiovascular calcium deposits, however the mechanism is in fact poorly understood (see Tomazic, B. B., In: Hydroxyapatite and Related Materials, pp. 93-115, P. W. Brown and B. Constantz, eds., CRC Press, Brown, Boca Ratan, Fla., 1994, herein incorporated by reference).
Surgical implantation of prosthetic devices (prosthesis) into humans and other mammals has been carried out with increasing frequency in the United States. Such protheses include heart valves, vascular grafts, urinary bladders, heart bladders, left ventricular-assist devices, hip prosthesis, breast implants, and tendon prosthesis, amongst others. At least forty models of substitute heart valves, including mechanical and bioprosthetic valves, have been used in the United States. Mechanical heart valve prostheses typically are composed of rigid materials such as polymers and metals, and use a poppet occluder which responds to changes in intracardiac pressure or flow. Bioprostheses have also been utilized for the replacement of heart valves. These are usually fabricated from porcine aortic valves or bovine epicardium, although only the porcine aortic valve or, occasionally, valves fashioned from human tissue, are used in the United States (see Hancock, E. W., in: Scientific American Medicine, Vol. 1, Section 1, Ch. IX, pp. 1-16, D. C. Dale and D. D. Friedman (eds)., Scientific American, N.Y., 1997).
Bioprostheses are typically pretreated with glutaraldehyde and then sewn onto a flexible metallic alloy or a flexible polymeric (plastic) stent which is then coved with a poly(ethylene terephthalate) cloth ring covering. Tissue valves are less likely than mechanical valves to produce thrombosis and systemic embolism. In addition, bioprostheses generally do not require routine anticoagulation. However, bioprostheses structurally deteriorate over time. This deterioration is usually related to mineralization (especially calcification) of the valve leaflets. Calcification is an important limitation on the useful life expectancy of bioprosthetic valves, and accounts for over sixty percent of the cardiac bioprostheses failures. Calcification of bioprosthetic valves develops more rapidly in children, which have an incidence of calcification of about 40% to 50% at four years. Adults have an incidence of calcification of between 5% to 20% at ten years (Carpentier, A., et al., Circulation 70 (suppl. I):I165-I168, 1984). Calcification causes thickening, retraction and reduced mobility of the leaflets and can lead to stenosis, insufficiency, or both. Currently, treatment of a functionally compromised bioprosthetic valve requires replacement with a new valve.
Several strategies to decrease or prevent mineralization of bioprosthetic heart valves have been described. Generally the methods involve treating the tissue with substances prior to implantation. Examples of pretreatment solutions to prevent calcification are a water-soluble phosphate ester (e.g., sodium dodecyl hydrogen phosphate, see U.S. Pat. No. 4,402,697), a water soluble quaternary ammonium salt (e.g., dodecyltrimethyammonium chloride, see U.S. Pat. No. 4,405,327), a sulfated higher aliphatic alcohol, (e.g., sodium dodecyl sulfate, see U.S. Pat. No. 4,323,358), or covalent coupling of an aliphatic carboxylic acid (see U.S. Pat. No. 4,976,733). Treatment of a bioprosthesis with a buffered solution having a pH in the range of 5.0 to 8.0, to generate an acellular graft prior to implantation (see U.S. Pat. No. 5,720,777) has also been described. However, none of these methods have proven successful in completely preventing mineralization. Thus, there remains a need for a postimplantation method useful in removing mineralized deposits on the tissue postimplantation.
Atherosclerotic calcification is an organized, regulated process similar to bone formation that occurs only when other aspects of atherosclerosis are also present. Calcium phosphate, in the crystalline form of carbonated apatite (dahllite), which contains 40% calcium by weight, precipitates in diseased coronary arteries by a mechanism similar to that found in active bone formation and remodeling (Bostom, K., et al., J. Clin. Invest. 91:1800-9, 1993; Lowenstam, H. A., and Wiener, S., On Biomineralization, Oxford University Press, N.Y). This was previously thought to be calcium phosphate (hydroxyapatite, Ca3[xe2x80x94PO4]2 Ca[OH]2). Atherosclerotic calcification begins as early as the second decade of life, just after fatty streak formation (Stary, H. C., Eur. Heart J. 11l(Suppl. E):3-19, 1990). The lesions of younger adults have revealed small aggregates of crystalline calcium phosphate among the lipid particles of lipid cores (Stary, H. C., et al., Circulation 92:1355-74, 1995). Calcific deposits are found more frequently and in greater amounts in elderly individuals and more advanced lesions (Doherty, T. M, and Detrano, R. C., Calcif. Tissue Int. 54:224-30, 1994). In most advanced lesions, when mineralization dominates the picture, components such as lipid deposits and increased fibrous tissue may also be present. The biochemical sequence of events leading to atherosclerotic calcification is not well understood.
Coronary artery calcification is potentially detectable in vivo by the following methods: plain film roentgenography; coronary arteriography; fluoroscopy, including digital subtraction fluoroscopy; cinefluorography; conventional, helical, and electron beam computed tomography (xe2x80x9cEBCTxe2x80x9d); intravascular ultrasound (xe2x80x9cIVUSxe2x80x9d); magnetic resonance imaging; and transthoracic and transesophageal echocardiography. In current practice, fluoroscopy and EBCT are most commonly used to detect coronary calcification noninvasively, while cinefluorography and IVUS are used by coronary interventionalists to evaluate calcification in specific lesions before angioplasty.
Histopathological investigation has shown that plaques with microscopic evidence of mineralization are generally larger and associated with larger arteries than are plaques or arteries without calcification. The relation of arterial calcification to the probability of plaque rupture is unknown. However, correlative studies indicate that patients with greater amounts of coronary calcification are more likely to suffer a clinical event compared with patients without calcification or lesser amounts (Detrano, R. C., et al., J. Am. Coll. Cardiol. 24:354-8, 1994). There is evidence linking radiographically detectable coronary calcium to future coronary heart disease events of death and infarction, which suggests that this link is strongest in symptomatic and very high-risk subjects (Naito, S., et al., J. Cardiol. 20:249-258, 1990).
This invention is based on the discovery that acid can be used to demineralize cardiovascular tissue in situ or in vitro, such as a calcified bioprosthetic heart valve or a calcified atherosclerotic lesion.
One aspect of the invention is a method for reducing mineralization of a cardiovascular tissue in a subject, by contacting the cardiovascular tissue with an acidic treatment solution for a period of time sufficient to reduce mineralization.
Another aspect of the invention is a balloon catheter assembly for infusion of a cardiovascular tissue having a mineralized area. This assembly comprises an elongated, flexible catheter having a relatively small diameter for insertion into the vessel and has two toroid-shaped balloons attached in series. These balloons have an inner surface, which is defined as the surface on the first balloon which faces the surface of the second balloon. In addition, an inflation means is communicatively connected with the first and second balloons which can be used to inflate the first and second balloons after insertion of the catheter into a vessel of the cardiovascular tissue, thus defining a segment of the vessel. The assembly also has an infusion means for infusing an acidic treatment material into the defined segment of the vessel, and an extraction means for extracting the acidic treatment material.
Another aspect of the invention is a method for infusing a demineralization solution into a cardiovascular tissue of a subject, comprising inserting a catheter into the cardiovascular tissue so that the catheter defines a blood flow passage, occluding a region within the cardiovascular tissue by inflating two balloons, one of which balloon defines the proximal end of the region and one of which defines the distal end of said region, and infusing an acidic treatment solution for a period of time sufficient to reduce mineralization.
In yet another embodiment a catheter assembly for infusion of a cardiovascular tissue is provided, where the tissue has a mineralized area. The catheter assembly includes a flexible catheter having a relatively small diameter for insertion into the vessel, where the flexible catheter has a flexible cup secured to the distal end of the catheter. A lumen extends through the flexible catheter and communicates with the flexible cup, such that an acidic treatment solution can be infused into an area defined by the cup.
In a further embodiment a catheter assembly for a valve that has a proximal side and a distal side, and a mineralized area, is provided. The assembly includes a flexible catheter with a first and a second lumen, where the distal end of first lumen is secured to a flexible cup which is placed adjacent to the proximal side of the valve when in use. The first lumen is operatively connected with a means for infusing an acidic treatment solution. The second lumen of the catheter extends through the valve. The distal end of the second lumen is secured to an additional flexible cup which is placed adjacent to the distal side of the valve when in use. An outlet exits on the second lumen, and the second lumen is operatively connected with an extraction means for removing the acidic treatment solution.